Effectiveness of Colonoscopy Screening vs Sigmoidoscopy Screening in Colorectal Cancer

Key Points Question What is the long-term additional benefit on colorectal cancer incidence and mortality associated with colonoscopy screening vs sigmoidoscopy screening? Findings This comparative effectiveness simulation study of 358 204 adults showed a statistically significant 7 percentage point reduction in colorectal cancer incidence and mortality at 15-year follow-up of colonoscopy screening, which proportionally amounted to 30% benefit compared with sigmoidoscopy screening. Meaning These findings suggest that the added benefit of colonoscopy screening is less than introducing sigmoidoscopy screening where no screening exists.

In brief, all trials included individuals aged 55-64 years at enrolment, randomised to once-only sigmoidoscopy screening or usual care (i.e.no screening invitation).The NORCCAP trial also included individuals aged 50-54 years and the PLCO trial included individuals aged 65-74 years (these age groups are not included in the current analysis).Individuals randomised to screening in PLCO were also offered a second sigmoidoscopy three or five years later. 1 In NORCCAP, 50% of individuals randomised to screening were asked to deliver a stool sample for one-time faecal immunochemical testing (FIT) on the day of the sigmoidoscopy.Screening in the trials was performed between 1993 and 2001.The primary endpoints in all trials were CRC incidence and mortality.
Participants in the control groups were not offered any intervention as part of the trials, but received health care, including similar access to cancer screening as the general population in each trial area.
All individuals in NORCCAP, UKFSST and SCORE with a positive sigmoidoscopy screening test were referred for colonoscopy (Figure 1).Individuals in PLCO with a positive screening test were referred to their primary care physician for follow-up.There were some differences between the trials in the definition of a positive screening test (eTable 1 in Supplement).
Details from the NordICC trial have been published previously. 2 In brief, screening-naïve individuals 55-64 years of age in Poland, Norway, Sweden, and the Netherlands were randomised 1:2 to once-only colonoscopy screening or usual care (no screening invitation).Screening was performed between 2009 and 2014 and primary endpoints were CRC incidence and mortality after 10 and 15 years.

eMethods 2. Details on data acquisition and data protection legislation
Due to new data protection legislation in Europe, individual patient data could not be shared across the trials and data therefore needed to be shared as aggregated anonymized data.
In the data from UKFSST, small numbers (7 or lower) could not be specified due to data protection legislation.Accordingly, the value "0-7" was given for any strata where fewer than eight events occurred.In the analyses, we used the value seven for these strata, which may overestimate the number of events; this applied to the screening and usual care group.

eMethods 3. Presentation of calculations to estimate screening effect on CRC incidence and mortality
Step 1: Sigmoidoscopy screening effect Cumulative incidence rates in sigmoidoscopy screening and usual care groups were calculated from the observed data in each trial.Rates were then used to calculate rate ratios (formula 1) and number of prevented events (CRC cases or CRC deaths) per 100 000 person-years (formula 2) by sigmoidoscopy screening compared to usual care.
Analysis groups according to manuscript Figure 1.
• Group [A] Individuals randomised to usual care (controls) • Group [B] Individuals randomised to sigmoidoscopy screening, but declined to undergo screening (non to attenders) • Group [C] Individuals randomised to sigmoidoscopy screening, attended screening, and had a positive screening test leading to a subsequent colonoscopy (screening positive)

PYr = person-year
Results from the individual trials were then pooled in a meta-analysis (the inverse to variance of the trial specific estimates as weights), to calculate rate ratios and number of prevented events per 100 000 person-years across trials.Variance of the overall estimate was the inverse of the sum of the weights.
Step 2: Colonoscopy screening effect Next, we wanted to estimate the additional number of events (CRC cases or CRC deaths) prevented with colonoscopy, compared to sigmoidoscopy.Estimates were calculated using the observed number of events in the proximal colon among screening negative (i.e.sigmoidoscopy screening attenders without subsequent colonoscopy, group [D] in manuscript Figure 1) and the sigmoidoscopy screening rate ratios for distal CRC (incidence or mortality).First, we calculated the number of proximal events prevented if colonoscopy had been used in the sigmoidoscopy screening negative individuals in each trial: The resulting numbers of events prevented were then subtracted from the observed total number of proximal events in the sigmoidoscopy screening arm to estimate the number of events if colonoscopy was used instead of sigmoidoscopy: Formula 4    ,   =    ,   −     ℎ We then used the resulting number of events in the colonoscopy screening group in each trial to calculate trial specific rate ratios (formula 5) and number of events prevented per 100 000 personyears (formula 6) by colonoscopy compared to usual care:

PYr = person-years
Finally, we pooled the results from the individual trials in a meta-analyses (again using the inverse-variance of trial specific estimates as weights) to calculate rate ratios and number of prevented events per 100 000 person-years across trials, variance of the overall estimate being again the inverse of the sum of the weights.Bootstrapping was used to estimate the variance of the colonoscopy metrics.

eMethods 4. Method description, validation of the simulation study
To validate the results from our simulation, we compared 10-year CRC incidence in the Norwegian sigmoidoscopy trial (NORCCAP) with the 10-year data from the Norwegian part of the NordICC colonoscopy trial. 3,4Participants in the two trials are comparable; they live in the same country, had the same age, and participation rates for screening were comparable (sigmoidoscopy: 65%, colonoscopy: 61%).Both screening tools were compared with usual care, and post-randomization consent was used in both trials.With a similar analytical approach as previously described (except we used individuals instead of personyears to make it comparable to NordICC), we simulated the colonoscopy screening effect in NORCCAP after 10-years follow-up, and compared the results to the observed results from the NordICC trial.The 10-year risk of CRC was 1.5% in the control groups in both the NORCCAP trial and the Norwegian part of the NordICC trial.In NORCCAP, the estimated effect of colonoscopy after 10-year follow-up was 26 (95% CI, 3-49) fewer CRC cases per 10 000 individuals, corresponding to a risk ratio of 0.83 (95% CI, 0.70-0.99).In comparison, the observed result from the Norwegian part of the NordICC trial was 37 (95% CI, 7-68) fewer CRC cases per 10 000 individuals, corresponding to a risk ratio of 0.76 (95% CI, 0.58-0.94). 4

Results of intention to treat analysis on CRC incidence and mortality after sigmoidoscopy or colonoscopy screening in each trial A. NORwegian Colorectal CAncer Prevention trial (NORCCAP)
Trial sigmoidoscopy screening effects are used to estimate the trial's colonoscopy screening effects.
*Participants randomized to flexible sigmoidoscopy were re to randomised 1:1 to receive a single faecal occult blood test (FOBT) or no additional testing.†Flexiblesigmoidoscopy was repeated at three or five years after baseline sigmoidoscopy.Screening attenders in the current study were individuals who were screened at baseline, and/or three or five years after baseline.‡Proportion of individuals who attended colonoscopy after a positive screening test among individuals invited to sigmoidoscopy screening.§The NORCCAP trial had pre to consent randomization which might affect attendance rate.eTable 3.

eTable 3 (cont'd). B. Prostate, Lung, Colorectal and Ovarian cancer screening trial (PLCO)
Trial sigmoidoscopy screening effects are used to estimate the trial's colonoscopy screening effects.Trial sigmoidoscopy screening effects are used to estimate the trial's colonoscopy screening effects.Trial sigmoidoscopy screening effects are used to estimate the trial's colonoscopy screening effects.
CI: confidence interval, CRC: colorectal cancer.*Number of individuals that need to switch screening method (from sigmoidoscopy to colonoscopy) to prevent one event.eTable 3 (cont'd).C. UK Flexible Sigmoidoscopy Screening Trial (UKFSST) CI: confidence interval, CRC: colorectal cancer.*Number of individuals that need to switch screening method (from sigmoidoscopy to colonoscopy) to prevent one event.eTable 3 (cont'd).D. Screening for Colon REctum trial (SCORE) CI: confidence interval, CRC: colorectal cancer.*Number of individuals that need to switch screening method (from sigmoidoscopy to colonoscopy) to prevent one event.eMethods 1.

Summary description of included endoscopy screening trials
Data used in our simulation analysis were from four randomized sigmoidoscopy screening trials in Norway (NORwegian Colorectal CAncer Prevention trial; NORCCAP) (ClinicalTrials.gov:NCT00119912), the US (Prostate, Lung, Colorectal and Ovarian cancer screening trial; PLCO) (ClinicalTrials.gov:NCT01696981), the UK (UK Flexible Sigmoidoscopy Screening Trial; UKFSST) (ISRCTN number: 28352761) and Italy (Screening for Colon REctum trial; SCORE) (ISRCTN number: 27814061).Additionaly, we used data from the Norwegian part the Nordic-European Initiative on Colorectal Cancer (NordICC) trial (ClinicalTrials.gov:NCT 00883792) on colonoscopy screening to validate our simulation model.All trials were approved by the ethics committees in the respective countries or regions.
• Group [D] Individuals randomised to sigmoidoscopy screening, attended screening, but did not have a subsequent colonoscopy (screening negative)